Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.

BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

Fc Receptor Inhibition Reduces Susceptibility to Oxidative Stress in Human RPE Cells Treated with Bevacizumab, but not Aflibercept.

BACKGROUND/AIMS: VEGF-A is induced by oxidative stress, and functions as a survival factor for various cell types, including retinal pigment epithelial (RPE) cells. Anti-vascular endothelial growth factor (VEGF) drugs like aflibercept and bevacizumab have shown to be most effective in treating neovascular age-related macular degeneration (AMD), however uptake of the drugs might lead to interference with cell physiology. Herein, we evaluated the significance of the Fc receptor (FcR) within this context and moreover explored the impact of VEGF inhibition under normal conditions as well as under oxidative stress, in terms of potential adverse effects. METHODS: ARPE-19 (human RPE) cells were treated with aflibercept and bevacizumab in presence or absence of H2O2 as oxidative stress stimulus. After 24h cells were evaluated for drug uptake, VEGF-A expression and secretion, levels of intracellular reactive oxygen species (ROS) as well as cell proliferation. Experiments were repeated with cells being pre-incubated with an FcR inhibitor prior to drug application. RESULTS: Both drugs inhibited extracellular levels of VEGF-A and were taken up into the RPE, resulting in significantly reduced intracellular levels of VEGF-A. When oxidative stress was applied, intracellular ROS levels in cells treated with both drugs rose, and cell proliferation was reduced. Prior incubation with the FcR inhibitor lessened the uptake of bevacizumab, but not aflibercept into RPE cells, and simultaneously enhanced cell survival under oxidative stress conditions. CONCLUSIONS: Our results indicate that uptake and accumulation of aflibercept and bevacizumab within RPE cells affect the intracellular VEGF-A metabolism negatively, leading to a biologically relevant reduced cell survival under oxidative stress. The FcR plays a substantial role in the uptake of bevacizumab, but not aflibercept, which allows an enhanced RPE cell survival through FcR blockage in an environment dominated by oxidative stress, as clinically significant for various inflammatory retinal disorders.

Intravitreal Aflibercept for Macular Edema Following Branch Retinal Vein Occlusion: 52-Week Results of the VIBRANT Study.

PURPOSE: To determine week 52 efficacy and safety outcomes in eyes with macular edema after branch retinal vein occlusion (BRVO) treated with 2 mg intravitreal aflibercept injection (IAI) compared with grid laser. DESIGN: VIBRANT was a double-masked, randomized, phase 3 trial. PARTICIPANTS: Eyes randomized and treated in VIBRANT were followed to week 52. METHODS: In the IAI group, eyes received IAI every 4 weeks through week 24 and IAI every 8 weeks through week 48 with rescue grid laser if needed at week 36. In the grid laser group, all eyes received grid laser at baseline and, if prespecified rescue criteria were met, 1 additional laser from week 12 to 20 and IAI every 8 weeks after 3 monthly doses from week 24 onward (the laser/IAI group). MAIN OUTCOME MEASURES: The primary outcome measure was percentage of eyes with improvement from baseline best-corrected visual acuity (BCVA) letter score ≥15 at week 24. All outcome measures at week 52 were exploratory, and P values are considered nominal. RESULTS: The percentage of eyes with improvement from baseline letter score ≥15 in the IAI and laser/IAI groups was 52.7% versus 26.7% (P = 0.0003) at week 24 and 57.1% versus 41.1% (P = 0.0296) at week 52. The corresponding mean change from baseline BCVA letter score was 17.0 versus 6.9 (P < 0.0001) at week 24 and 17.1 versus 12.2 (P = 0.0035) at week 52. The mean reduction from baseline central retinal thickness was 280.5 µm versus 128.0 µm (P < 0.0001) at week 24 and 283.9 µm versus 249.3 µm (P = 0.0218) at week 52. In the IAI group, 10.6% of eyes received rescue laser at week 36, and in the laser/IAI group, 80.7% received rescue IAI from week 24 to week 48. Traumatic cataract in 1 eye (1.1%) in the IAI group was the only ocular serious adverse event. CONCLUSIONS: After 6 monthly IAI, injections every 8 weeks maintained control of macular edema and visual benefits through week 52. In the laser group, rescue IAI given from week 24 onward resulted in substantial visual improvements at week 52.

Phase I Dose-Escalation and Pharmacokinetic Study of Intravenous Aflibercept in Combination with Docetaxel, Cisplatin, and 5-Fluorouracil in Patients with Advanced Solid Malignancies.

PURPOSE: This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated. RESULTS: Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease. CONCLUSION: Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity.

Incidence and risk of severe infections associated with aflibercept in cancer patients: a systematic review and meta-analysis.

AIMS: Aflibercept is an engineered humanized vascular endothelial growth factor (VEGF)-targeted agent. Severe infections are serious adverse event associated with aflibercept. However, the contribution of aflibercept to infection is still unknown. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing severe infections in cancer patients treated with aflibercept. METHODS: Electronic databases including PubMed, Embase and abstracts presented at American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meeting were searched. Eligible studies were phase II and III prospective clinical trials of aflibercept in cancer patients with toxicity profile on infections. Summary incidences, relative risk (RR), odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS: A total of 4310 patients with a variety of solid tumours from 10 prospective clinical trials were included in the meta-analysis. The incidence of high grade infections associated with aflibercept was 7.3% (95% CI 4.3, 12.0%), with a mortality of 2.2% (95% CI 1.5, 3.1%). In addition, patients treated with aflibercept had a significantly increased risk of developing high grade (RR 1.87, 95% CI 1.52, 2.30; P < 0.001) and fatal (OR 2.16, 95% CI 1.14, 4.11; P = 0.018) infections. No evidence of publication bias was observed. Furthermore, the risk of infections with aflibercept was substantially higher than bevacizumab. CONCLUSIONS: Aflibercept is associated with a significant increased risk of developing severe infections in patients with solid tumours. Frequent clinical monitoring and appropriate management for infections should be emphasized during aflibercept treatment.

Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.

BACKGROUND: Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC. METHODS: Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs). RESULTS: Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs. CONCLUSIONS: This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.

Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 24-week results of the VIBRANT study.

PURPOSE: To compare the efficacy and safety of intravitreal aflibercept injection (IAI) with macular grid laser photocoagulation for the treatment of macular edema after branch retinal vein occlusion (BRVO). DESIGN: The VIBRANT study was a double-masked, active-controlled, randomized, phase III trial. PARTICIPANTS: Treatment-naïve eyes with macular edema after BRVO were included in the study if the occlusion occurred within 12 months and best-corrected visual acuity (BCVA) was between ≤73 and ≥24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (20/40-20/320 Snellen equivalent). METHODS: Eyes (1 eye per patient) received either IAI 2 mg every 4 weeks (n=91) from baseline to week 20 or grid laser (n=92) at baseline with a single grid laser rescue treatment, if needed, from weeks 12 through 20. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of eyes that gained ≥15 ETDRS letters from baseline BCVA at week 24. Secondary end points included mean change from baseline BCVA and central retinal thickness (CRT) at week 24. RESULTS: The proportion of eyes that gained ≥15 ETDRS letters from baseline at week 24 was 52.7% in the IAI group compared with 26.7% in the laser group (P=0.0003). The mean improvement from baseline BCVA at week 24 was 17.0 ETDRS letters in the IAI group and 6.9 ETDRS letters in the laser group (P<0.0001). The mean reduction in CRT from baseline at week 24 was 280.5 µm in the IAI group and 128.0 µm in the laser group (P<0.0001). Traumatic cataract in an IAI patient was the only ocular serious adverse event (SAE) that occurred. There were no cases of intraocular inflammation or endophthalmitis. The incidence of nonocular SAEs was 8.8% in the IAI group and 9.8% in the laser group. One Anti-Platelet Trialists' Collaboration-defined event of nonfatal stroke (1.1%) and 1 death (1.1%) due to pneumonia occurred during the 24 weeks of the study, both in patients in the laser group. CONCLUSIONS: Monthly IAI provided significantly greater visual benefit and reduction in CRT at 24 weeks than grid laser photocoagulation in eyes with macular edema after BRVO.

Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies.

PURPOSE: To compare efficacy and safety of 2 dosing regimens of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME). DESIGN: Two similarly designed, randomized, phase 3 trials, VISTA(DME) and VIVID(DME). PARTICIPANTS: Patients (eyes; n=872) with type 1 or 2 diabetes mellitus who had DME with central involvement. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. MAIN OUTCOME MEASURES: The primary end point was mean change from baseline in best-corrected visual acuity (BCVA) at week 52. This report presents the 100-week results including mean change from baseline in BCVA, proportion of eyes that gained ≥15 letters, and proportion of eyes with a ≥2-step improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. RESULTS: Mean BCVA gain from baseline to week 100 with IAI 2q4, IAI 2q8, and laser control was 11.5, 11.1, and 0.9 letters (P < 0.0001) in VISTA and 11.4, 9.4, and 0.7 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 100 was 38.3%, 33.1%, and 13.0% (P < 0.0001) in VISTA and 38.2%, 31.1%, and 12.1% (P ≤ 0.0001) in VIVID. The proportion of eyes that lost ≥15 letters at week 100 was 3.2%, 0.7%, and 9.7% (P ≤ 0.0220) in VISTA and 2.2%, 1.5%, and 12.9% (P ≤ 0.0008) in VIVID. Significantly more eyes in the IAI 2q4 and 2q8 groups versus those in the laser control group had a ≥2 step improvement in the DRSS score in both VISTA (37.0% and 37.1% vs. 15.6%; P < 0.0001) and VIVID (29.3% and 32.6% vs. 8.2%; P ≤ 0.0004). In an integrated safety analysis, the most frequent serious ocular adverse event was cataract (2.4%, 1.0%, and 0.3% for 2q4, 2q8, and control). CONCLUSIONS: In both VISTA and VIVID, the 52-week visual and anatomic superiority of IAI over laser control was sustained through week 100, with similar efficacy in the 2q4 and 2q8 groups. Safety in these studies was consistent with the known safety profile of IAI.

Intraocular Pressure in Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept or Ranibizumab.

PURPOSE: To assess change in intraocular pressure (IOP) in patients with neovascular age-related macular degeneration (NVAMD) receiving intravitreal aflibercept injection (IAI) or ranibizumab in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies. DESIGN: Analyses from 2 randomized, active-controlled, phase III trials. PARTICIPANTS: A total of 2457 patients with NVAMD. METHODS: Patients received IAI 2 mg every (q) 4 weeks (2q4), 0.5 mg q4 weeks (0.5q4), 2 mg q8 weeks (after 3 monthly doses; 2q8), or ranibizumab 0.5 mg q4 weeks (Rq4) for 52 weeks. At week 52, patients were switched to a variable regimen requiring at least quarterly dosing and allowing interim injections based on anatomic and visual assessment. MAIN OUTCOME MEASURES: Pre-injection IOP was analyzed in study and uninjected fellow eyes from baseline to week 96. Prespecified end points included mean change in IOP from baseline and prevalence of a >21 mmHg and >10 mmHg increase in IOP from baseline. Cumulative incidence of sustained (at 2 consecutive visits) IOP >21 mmHg, a single event of IOP >25 mmHg, and sustained IOP increase from baseline (≥5 mmHg) was also evaluated. RESULTS: Mean IOP change from baseline over 96 weeks in all IAI groups was consistently lower than in the Rq4 group, and this finding was replicated in both trials. In an analysis integrating both studies, the proportion of study eyes with IOP >21 mmHg at week 96 was 20.2%, 14.2%, 12.1%, and 12.5% in Rq4, 2q4, 2q8, and 0.5q4, respectively. Reduction in risk, relative to Rq4, of having sustained IOP >21 mmHg over 96 weeks was 62% (95% confidence interval [CI], 36%-78%), 50% (95% CI, 19%-70%), and 69% (95% CI, 45%-84%) for 2q4, 2q8, and 0.5q4, respectively. Risk reduction in the IAI groups for a sustained IOP increase ≥5 mmHg was 31% (95% CI, 8%-48%), 38% (95% CI, 17%-54%), and 47% (95% CI, 27%-61%), respectively. In uninjected fellow eyes, only sustained IOP >21 mmHg events were higher in the Rq4 group compared with all IAI groups. CONCLUSIONS: Incidence of elevated IOP in eyes with NVAMD was lower in all IAI groups than in the ranibizumab group.

Therapies for macular edema associated with central retinal vein occlusion: a report by the American Academy of Ophthalmology.

PURPOSE: To review the available evidence regarding the safety and efficacy of therapies for the treatment of macular edema (ME) associated with central retinal vein occlusion (CRVO). METHODS: A literature search of the PubMed database was last conducted in March 2014 with no date restrictions but limited to articles published in English. A literature search of the Cochrane Library was also conducted in March 2014 with no date restrictions and without a language limitation. The combined searches yielded 108 citations, of which 20 were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous panel to review in full text. Three additional studies were also identified for panel review. The level of evidence of these selected studies was reviewed by the panel methodologist. RESULTS: There were 7 citations representing 4 clinical trials that provided level I evidence supporting the use of anti-vascular endothelial growth factor (VEGF) pharmacotherapies for ME associated with CRVO, including intravitreal ranibizumab (2), aflibercept (3), and bevacizumab (2). There were 3 citations representing 2 studies with level I evidence for intravitreal corticosteroid injection with dexamethasone intravitreal implant (2 citations) or triamcinolone (1 citation), although cataract and glaucoma were observed in these studies. Level I evidence is available on the limited benefit of macular grid-pattern laser photocoagulation (1 citation). Eight other citations reviewed were rated as level II, and 4 citations were rated as level III. Long-term efficacy results (≥2 years of follow-up) are limited to intravitreal ranibizumab at this time, and few studies have evaluated combination therapy with anti-VEGF and corticosteroid versus monotherapy of either class of drug. CONCLUSIONS: Level I evidence indicates that intravitreal anti-VEGF pharmacotherapy is safe and effective over 2 years for ME associated with CRVO and that delay in treatment is associated with worse visual outcomes. In addition, level I evidence demonstrates short-term efficacy of intravitreal corticosteroid but also an association with a higher frequency of adverse events.

Fluorouracil, leucovorin and irinotecan associated with aflibercept can induce microscopic colitis in metastatic colorectal cancer patients.

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF). This molecule binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, preventing them from activating their respective receptors. Aflibercept is used for the treatment of metastatic colorectal cancer (mCRC) in association with irinotecan. For reasons that remain to be elucidated, the addition of aflibercept to irinotecan-based chemotherapy increases the incidence of grade 3-4 diarrhea. We performed systematic colonic biopsies in three patients with grade 3 diarrhea after introduction of fluorouracil, leucovorin, irinotecan and aflibercept treatment for mCRC. For each patient, the diarrhea necessitated treatment discontinuation. Colonoscopy showed normal colonic mucosa. However, histopathological examination of the biopsies performed in these three patients revealed typical features of microscopic colitis. All three patients were treated with budesonide and mesalazine, leading to rapid regression of clinical symptoms. Chemotherapy was reintroduced in all patients, with only mild, grade 1 diarrhea under mesalazine and budesonide treatment. These are the first observations of aflibercept-induced microscopic colitis, and support the use of specific treatment on top of anti-diarrheal treatment in case of important digestive adverse events.

Microperimetric assessment of retinal sensitivity in eyes with diabetic macular edema from a phase 2 study of intravitreal aflibercept.

PURPOSE: To evaluate retinal sensitivity in patients with diabetic macular edema who received intravitreal aflibercept injection (IAI) or laser. METHODS: A substudy included 46 patients from DA VINCI (a randomized, double-masked Phase 2 study) receiving either laser, 0.5 mg IAI every 4 weeks, 2 mg IAI every 4 weeks, 2 mg IAI every 8 weeks after 3 monthly doses (2q8), or 2 mg IAI as-needed after 3 monthly doses for 52 weeks. Retinal sensitivity was measured in one (central), five (one central and four inner), and eight (four inner and four outer) optical coherence tomography subfields. RESULTS: Mean best-corrected visual acuity improvement in the subgroup at Week 52 was 3.3 letters with laser and ranged from 5.4 to 16.3 letters in the IAI groups. Retinal sensitivity of laser patients at Week 52 was comparable with baseline in the central optical coherence tomography subfield but decreased in the five and eight optical coherence tomography subfields. Compared with laser, retinal sensitivity significantly increased with IAI in the 2q8 and pooled IAI groups in the 5 and 8 optical coherence tomography subfields at Week 52 (P < 0.05). CONCLUSION: Intravitreal aflibercept injection improved best-corrected visual acuity and retinal sensitivity in this subgroup of patients. Laser may cause a deterioration of macular function that is not detectable with best-corrected visual acuity testing.

Frequency and characteristics of intraocular inflammation after aflibercept injection.

PURPOSE: To report the frequency and characteristics of intraocular inflammation after intravitreal aflibercept injection. METHODS: A single-center retrospective study was performed in patients who received intravitreal aflibercept from November 2011 through June 2013. RESULTS: There were 28 cases of intraocular inflammation after a total of 5,905 aflibercept injections among 1,660 patients. The mean baseline acuity was 20/57, which decreased to 20/179 at diagnosis (P < 0.0001) but recovered to 20/59 at Month 1, 20/57 at Month 3, and 20/52 at Month 6 (P = not significant). Vitreous culture and injection of antibiotics were performed in eight cases, and all were culture negative; the remainder received only topical corticosteroids. CONCLUSION: The frequency of inflammation after aflibercept was 0.47% per injection. Visual acuity and inflammation returned to baseline within 1 month in most cases with topical corticosteroid treatment.

ASSOCIATION BETWEEN NEEDLE SIZE, POSTINJECTION REFLUX, AND INTRAOCULAR PRESSURE SPIKES AFTER INTRAVITREAL INJECTIONS.

PURPOSE: To compare the effect of 30-gauge versus 32-gauge needle size on postinjection reflux and immediate postinjection intraocular pressure (IOP(immed_post)) spikes in eyes injected with anti-vascular endothelial growth factor agents. METHODS: This was a prospective interventional case series of 65 eyes of 54 consecutive patients in a clinical practice setting who received intravitreal anti-vascular endothelial growth factor therapy. All eyes had preinjection IOP, IOP(immed_post), postinjection reflux, and axial lengths recorded. RESULTS: There was a higher incidence of postinjection reflux in eyes injected with 30-gauge (53%) compared with those injected with 32-gauge (13%, P = 0.0007). Among 34 eyes injected with 30-gauge, 16 eyes without appreciable postinjection reflux had mean IOP(immed_post) of 44.3 ± 7.48 mmHg and mean IOP(immed_post) elevation of 29.6 ± 2.10 mmHg, which was significantly higher than the 18 eyes with reflux (mean IOP(immed_post) of 18.8 ± 7.15 mmHg and mean IOP(immed_post) elevation of 4.5 ± 1.74 mmHg, P < 0.0001). Among 31 eyes injected with 32-gauge, 27 eyes without appreciable postinjection reflux had mean IOP(immed_post) of 44.4 ± 10.82 mmHg and mean IOP(immed_post) elevation of 29.5 ± 1.99 mmHg, which was significantly higher than the 4 eyes with reflux (mean IOP(immed_post) of 21.3 ± 8.54 mmHg and mean IOP(immed_post) elevation of 9.5 ± 4.05 mmHg, P < 0.001). The differences in reflux and IOP between the two groups were unrelated to axial lengths (P = 0.451). CONCLUSION: Eyes receiving injections with 32-gauge needles had a lower incidence of postinjection reflux and higher mean IOP immediately after injection.

Full thickness macular hole case after intravitreal aflibercept treatment.

BACKGROUND: The pathogenesis of macular hole formation is widely accepted as a tractional force at the vitreo-retinal interface in fovea. We report a case of macular hole after intravitreous aflibercept injection for age-related macular degeneration (AMD) associated with contraction of the retinal pigment epithelium (RPE) at the edge of a fibrovascular pigment epithelial detachment (PED). CASE PRESENTATION: A 94-year old man with neovascular AMD affecting his left eye accompanied by a fibrovascular PED was examined for severe vision loss. Although RPE tear in his left eye was identified before the first aflibercept intravitreous injection performed in order to treat neovascular AMD, he received three aflibercept injections as induction treatment. After induction treatment, a full thickness macular hole was identified associated with the contracted rolled RPE edge beneath the retina. CONCLUSION: Macular hole is commonly formed associated with tangential vitreous traction. Current report suggests that rapid contraction of the RPE underneath the retina can be one of the causes of a macular hole, and one of the side effects of anti-VEGF therapy for neovascular AMD.

Intravitreal Aflibercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 12-Month Safety and Efficacy Outcomes.

PURPOSE: To prospectively assess the safety and efficacy of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD). METHODS: This prospective, non-randomized clinical trial included 49 patients with treatment-resistant nAMD who received 2 mg intravitreal aflibercept as 3 monthly loading doses, followed by injections every 2 months over 12 months. Inclusion criteria included active nAMD on fluorescein angiography at baseline and persistent intra- or subretinal fluid on optical coherence tomography (OCT) for ≥ 6 months prior to baseline with a minimum of 4 injections of bevacizumab and/or ranibizumab. Patients were assessed monthly for best-corrected visual acuity (BCVA), central retinal thickness (CRT) measured with OCT and occurrence of adverse events. Retinal pigment epithelium atrophy (RPEA) was assessed at baseline and at 12 months. RESULTS: Mean BCVA improved by 4.7 letters (95% CI: 2.1-7.3, p < 0.001) and CRT decreased by 97.2 µm (95% CI: 54.4-140.1, p < 0.001) at 12 months compared to baseline. Median RPEA area increased by 0.48 mm2 (range = -0.1 to 19.9, p < 0.001). There was 1 arterial thromboembolic event and 2 cases of submacular haemorrhage. CONCLUSION: In this cohort of treatment-resistant nAMD patients, intravitreal aflibercept was effective in improving vision and reducing exudation. Early visual and anatomic outcomes may predict longer-term response to treatment, but further assessment is required.

Ischaemic stroke after exposure to aflibercept: interaction with vitamin K antagonist and/or direct pharmacodynamic effect?

WHAT IS KNOWN AND OBJECTIVE: Vascular endothelial growth factor (VEGF) proteins are involved in the regulation of vascular endothelium, and their inhibition led to the development of a number of drugs used for malignancies or exudative neo-vascular age-related macular degeneration (AMD). CASE SUMMARY: We report a case of ischemic stroke in an 87-year-old woman having received intravitreal aflibercept, a new anti-VEGF for AMD. She had been treated with ranibizumab since 2007. In 2013, ranibizumab was replaced with aflibercept, followed by a decrease in the International Normalized Ratio, complicated by a stroke a few days later. The rechallenge was positive. WHAT IS NEW AND CONCLUSION: A potential time-dependent interaction between aflibercept and VKA antagonist and/or a direct effect of aflibercept may have contributed to the occurrence of the ischaemic stroke. Currently available data suggest some pharmacokinetic and pharmacodynamic effects of aflibercept by explaining its pro-thrombotic profile.

Aflibercept (Eylea) and diabetic macular oedema. A first-choice VEGF inhibitor in case of marked visual loss.

Overall, VEGF inhibitors administered by intravitreal injection have a similar harm-benefit balance. However, a publicly funded trial has shown that aflibercept is more effective than ranibizumab and bevacizumab in patients with marked loss of visual acuity.

Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallel-arm study.

BACKGROUND: In this randomized phase 2 study, the authors assessed the efficacy and safety of intravenous aflibercept at 2 different doses (2 mg/kg or 4 mg/kg) in patients with recurrent, platinum-resistant ovarian, peritoneal, or fallopian tube cancer who developed disease progression after receiving topotecan and/or pegylated liposomal doxorubicin. METHODS: Patients were randomized to receive intravenous aflibercept at a dose of either 2 mg/kg or 4 mg/kg every 2 weeks until they developed disease progression or significant toxicity. The primary endpoint was to evaluate Response Evaluation Criteria in Solid Tumor response rates (overall response rate [ORR] = complete responses plus partial responses) and to test the null hypothesis (ORR, >5%). Secondary endpoints included time to tumor progression, safety, progression-free survival/overall survival, drug pharmacokinetics, and immunogenicity. In total, 67 evaluable patients per cohort were planned based on a Simon 2-stage design, and, if those patients responded, then enrollment could extend to 200 patients. Tumor radiographic response was assessed by investigators and by an independent review committee. RESULTS: After the first 84 evaluable patients, 8 unconfirmed partial responders were noted (ORR, 10%) across both arms; the Independent Data Monitoring Committee recommended continuing blinded accrual. At study completion, 215 evaluable patients were accrued, including 1 responder of 106 patients (0.9%) in the 2-mg/kg cohort and 5 responders of 109 patients (4.6%) in the 4-mg/kg cohort according to the independent review committee. The clinical benefit rate (ORR plus stable disease >6 months) was 12.3% and 11% in the 2-mg/kg and 4-mg/kg cohorts, respectively. Treatment-related grade 3 and 4 adverse events included hypertension (25.5% and 27.5% in the 2-mg/kg and 4-mg/kg cohorts, respectively), proteinuria (9.4% and 7.3%, respectively), and fatigue (5.7% and 3.7%, respectively). The gastrointestinal perforation rate was low (3 patients; 1.4%). CONCLUSIONS: Aflibercept at a dose of either 2 mg/kg or 4 mg/kg was generally well tolerated but did not meet the primary endpoint for response.

A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer.

BACKGROUND: This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC). METHODS: This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients. RESULTS: The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months. CONCLUSION: Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.